Hallucinations (sensory perceptions in the absence of any external stimulus) are severe and frequent symptoms, affecting an estimated three (3) million patients with Parkinson's disease and 30 million patients with schizophrenia worldwide and causing major health costs in Europe and the United States alone, respectively $23 billion and $120 billion per year. Despite increased efforts in neuroscience research, current understanding in neuroscience about hallucinations is still limited and diagnosis and therapy for hallucinations remains challenging. Strikingly, diagnosis of hallucinations still relies on subjective verbal descriptions of the patient and correct classification by the physician, differing from the symptoms of most medical conditions that are quantified based on biomedical markers.
Parkinson's disease (PD) is a chronic and progressive disorder of the central nervous system that primarily affects the motor system. More than 7 million people worldwide suffer from PD, and approximately 60,000 Americans are newly diagnosed with PD each year. PD is associated with an estimated direct and indirect health cost of nearly $23 billion per year in the United States and Europe alone, including treatment, social security payments, lost income from inability to work, and others.
Although in the early stages of the disease most of the major symptoms are related to the motor system (tremor, bradykinesia, muscle stiffness), the large majority of PD patients in later stages of the disease suffer from moderate to severe cognitive disturbances and/or hallucinations (Diederich et al., “Hallucinations in Parkinson disease,” Nature Reviews Neurology, Vol. 5, Iss. 6, pp. 331-342, 2009). Motor symptoms are caused by loss of dopamine neurons in the substantia nigra and well-defined alterations in subcortical motor networks (Agid, Yves, “Parkinson's disease: pathophysiology,” The Lancet 337, No. 8753, 1991, pp. 1321-1324). The cognitive disturbances and especially hallucinations in PD patients are less well investigated and their underlying brain mechanisms are currently unclear. This is unfortunate given their prominence in later phases of PD and their negative prognostic value.
Hallucinations, defined as sensory perceptions without any external stimulus, are an extremely common feature of PD, affecting approximately 50% of patients (Wood et al., “Fifty percent prevalence of extracampine hallucinations in Parkinson's disease patients,” Frontiers in Neurology, Vol. 6, 2015, p. 263). As mentioned, the presence of hallucinations has been shown to be of negative prognostic value as they are associated with an increased risk of dementia, depression, and other cognitive deficits, nursing home placement, and death. One particular type of minor hallucination called the feeling of a presence (FoP) is defined as the sensation that somebody is nearby when no one is actually present. FoP is not only recognized as the most prevalent hallucination in PD, but also as a precursor of other types of major hallucinations, including psychotic symptoms and has recently been included in the new diagnostic criteria for PD-associated psychosis (Ravina et al., “Diagnostic criteria for psychosis in Parkinson's disease: report of an NINDS, NIMH work group,” Movement Disorders Vol. 22, No. 8, 2007, pp. 1061-1068).
However, the detailed relations between FoP and major hallucinations remain uncertain. FoP is important for two main reasons: to reassure the patient that FoP is not uncommon in PD, and that they are not terrible hallucinations) and to have the physician realize that increasing PD medication may induce hallucinations and hence such symptoms are a warning. In current medical practice, despite the fact that hallucinations are key symptoms in PD, their clinical assessment is based upon semi-structured interviews between patient and physician and relies on the patient's verbal account and the physician's correct classification and diagnostic application. In a prospective analysis in incident, untreated PD patients, Pagonabarraga et al. characterized the FoP as a frequent and very early non-motor symptom that may even predate the onset of parkinsonian motor symptoms (Pagonabarraga et al., “Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase,” Movement Disorders, Vol. 31, No. 1, 2016, pp. 45-52). In another study, Wood et al. outlined that the onset of visual hallucinations commonly precedes that of cognitive impairment in PD, pinpointing on the need of prospective natural history studies of extracampine hallucinations, including FoP), in PD patients without cognitive impairment, forecasting that visual hallucinations would be preceded by the occurrence of extracampine hallucinations. (Wood et al., “Fifty percent prevalence of extracampine hallucinations in Parkinson's disease patients,” Frontiers in neurology, Vol. 6, Iss. 263, 2015, p. 1).
As it is evident, all these studies are statistical prospective studies, which are prone to errors due to the subjective interpretation of the physician, the possibly incorrect report of the patient and the criteria for exclusion/inclusion of a patient in the study.
This clearly differs from most symptoms in medicine, including the motor symptoms in PD, that can be quantified to e.g. guide diagnostics and the choice of the proper medical treatment. Accordingly, there are currently no biological markers for hallucinations in PD, or any other diseases with hallucinations, although such markers are needed to detect PD patients with hallucinations and other related consequences, such as dementia, home placement, depression, death, as early as possible to e.g. adapt medical treatments. Of note, such patient-physician interviews are almost never carried out while the patient actually suffers from hallucinations; hallucinations may have occurred days, weeks, or months earlier and therefore correct medical classification relies in addition on a patient's correct memory and verbal description of the hallucinations to the physician.
There are currently no medically accepted procedures allowing to induce the FoP or hallucinations in PD patients under safe and controlled conditions. This has limited basic neuroscience research to understand the brain mechanisms underlying hallucinations and also hindered the development of related diagnostic and therapeutic procedures that could replace, improve, or complement existing pharmacological treatments that have many serious medical side effects. Accordingly, in light of the above deficiencies of the background art, novel and substantially improved procedures and methods FOR predicting the likelihood of the occurrence of hallucinations are strongly desired.